BACKGROUND: Liposomal amphotericin-B (Ambisome(®)) is widely used antifungal drug for treatments of invasive fungal infections. The use of liposomal amphotericin-B is increasing in medical setting because of its tolerability and potent antifungal activity. CASE PRESENTATION: In a case of a 76 year-old Japanese female was admitted with subarachnoid hemorrhage, the ethnicity of the patient is Asian, we experienced that liposomal amphotericin-B was the culprit drug for Drug-induced hypersensitivity syndrome, also known as drug rash with eosinophilia and systemic symptoms in view of a clear temporal relationship between liposomal amphotericin-B administration and the onset of symptoms, the remission of the symptomatological pattern after liposomal amphotericin-B withdrawal. CONCLUSION: The present case report shows that prolonged liposomal amphotericin-B treatment can be associated with drug rash with eosinophilia and systemic symptoms. We recommend careful monitoring of neutrophil counts in a prolonged treatment course with liposomal amphotericin-B

Hideo Kato

Hiroshige Mikamo

Jun Hirai

Katsuhiko Matsuura

Mao Hagihara

Yuka Yamagishi

Yukihiro Hamada

Yusuke Koizumi

BMC Research Notes

PubMed

Springer - Publisher Connector

Hagihara et al. BMC Res Notes  (2015) 8:510 
DOI 10.1186/s13104-015-1486-0
CASE REPORT
Drug-induced hypersensitivity 
syndrome by liposomal amphotericin-B: a case 
report
Mao Hagihara1,2, Yuka Yamagishi1, Jun Hirai1, Yusuke Koizumi1, Hideo Kato1,2, Yukihiro Hamada1,2, 
Katsuhiko Matsuura1,2 and Hiroshige Mikamo1*
Abstract 
Background: Liposomal amphotericin-B (Ambisome®) is widely used antifungal drug for treatments of invasive 
fungal infections. The use of liposomal amphotericin-B is increasing in medical setting because of its tolerability and 
potent antifungal activity.
Case presentation: In a case of a 76 year-old Japanese female was admitted with subarachnoid hemorrhage, the 
ethnicity of the patient is Asian, we experienced that liposomal amphotericin-B was the culprit drug for Drug-induced 
hypersensitivity syndrome, also known as drug rash with eosinophilia and systemic symptoms in view of a clear tem-
poral relationship between liposomal amphotericin-B administration and the onset of symptoms, the remission of the 
symptomatological pattern after liposomal amphotericin-B withdrawal.
Conclusion: The present case report shows that prolonged liposomal amphotericin-B treatment can be associated 
with drug rash with eosinophilia and systemic symptoms. We recommend careful monitoring of neutrophil counts in 
a prolonged treatment course with liposomal amphotericin-B.
Keywords: Liposomal amphotericin-B, Drug-induced hypersensitivity syndrome (DIHS), Drug rash with eosinophilia 
and systemic symptoms (DRESS)
© 2015 Hagihara et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License 
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, 
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, 
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Background
Drug-induced hypersensitivity syndrome (DIHS), also 
known as drug rash with eosinophilia and systemic symp-
toms (DRESS), is a severe adverse drug reaction [1–3]. Its 
true incidence is unknown, but it has been estimated to 
occur at the frequency of 1 in 1000 to 1 in 10,000 expo-
sures to high-risk drugs [4]. DRESS syndrome char-
acterized by fever, skin rash, and facial edema, organ 
involvement such as hepatitis or nephritis. Lymphad-
enopathy and splenomegaly may occur. The syndrome 
occurs within 2–6  weeks after initiating drug treatment 
[5].
Liposomal amphotericin-B (L-AMB; Ambisome®) is 
widely used antifungal drug for treatments of invasive 
fungal infections [6]. This lipid formulation consists of 
amphotericin-B embedded in the wall of a unilamellar 
liposome. A regimen of 2.5–5 mg/kg of body weight/day 
is effective for treatments of invasive infections caused 
by Candida spp. and Aspergillus spp. [7, 8]. L-AMB is 
also used for treatments of Cryptococcal meningitis and 
mucormycosis [9, 10]. Most noteworthy side effects of 
L-AMB are hypokalemia and renal insufficiency. Other 
side-effects, definitely attributed to L-AMB therapy, are 
low back pain, nausea and vomiting, confusion, rise in 
alkaline phosphatase, and cholecystitis. However, hyper-
sensitivity with rash and pruritus has been described in 
rare cases [11]. We report here a clinical observation of 
L-AMB-induced DRESS.
Open Access
*Correspondence:  mikamo@aichi-med-u.ac.jp 
1 Department of Infection Control and Prevention, Aichi Medical 
University School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi 
480-1195, Japan
Full list of author information is available at the end of the article
Page 2 of 4Hagihara et al. BMC Res Notes  (2015) 8:510 
Case presentation
A 76 year-old Japanese female with no known drug aller-
gies was admitted with subarachnoid hemorrhage (SAH). 
The ethnicity of the patient was Asian. Her medical his-
tory showed rheumatoid arthritis; anti-inflammatory 
drug was done with prednisolone (1  mg/day). The per-
sistent high fever and candidemia were admitted after 
coil embolization for SAH. The patient was prescribed 
Fosfluconazole (F-FLCZ) at 400  mg/day. One month 
after the surgery, she had been described as mycotic 
endophthalmitis with Candida parapsilosis. [Minimum 
inhibitory concentration (MIC) detected by broth micro-
dilution method according to Clinical and Laboratory 
Standards Institute (CLSI) 94 M27-A3 guideline for sev-
eral antifungal drugs are as follows; 5-flucytosin (5-FC): 
≤0.125 μg/mL, amphotericin-B (AMPH-B): 0.25 μg/mL, 
fluconazole (FLCZ): 0.125 μg/mL, voriconazole (VRCZ): 
≤0.015 μg/mL, micafungin (MCFG): ≤0.03 μg/mL] The 
summary of antibiotic treatments and laboratory results 
given in Fig.  1. Because of persistent high fever, candi-
demia and exacerbation of patient’s clinical condition, 
the antifungal drug was switched to L-AMB 100  mg/
day (3  mg/kg: infusion time was about 2  h) and 5-FC 
3000  mg/day. She had been administrated L-AMB and 
5-FC for 58 and 37 days. Forty-five days after start of the 
antifungal combination therapy, the patient was fever-
ish with an exanthema of the trunk, arms and legs, and 
skin rash appeared. Then, we suspected that 5-FC was 
the cause drug and 5-FC was ceased. But she had been 
admitted persistent feverish with an exanthema during 
L-AMB therapy continued. Her condition has clinically 
improved with only residual hyper pigmentation after 
stopped all antibiotics including L-AMB.
One month after the event, she had been admitted per-
sistent high fever and re-prescribed L-AMB at 100  mg/
day as a prophylactic antifungal drug for candidemia. 
Right after re-start of the drug therapy, the patient was 
feverish with an exanthema of the trunk, arms and legs 
again (Fig. 2). On the physical examination, her tempera-
ture was over 38.0  °C and a generalized, diffuse, macu-
lopapular, erythematous, petechial, pruritic rash was 
noted over the face, trunk, and extremities with marked 
facial edema, while there was no blister. A maculopapu-
lar eruption was noted. The mucosa was not affected, as 
Sulbactam/Ampicillin
L-amphotericin B
5-flucytosin
fosfluconazole
Levofloxacin
Daptomycin
Minomycin
Meropenem
Teicoplanin
Tazobactam/Piperacillin
0
0.2
0.4
0.6
0.8
0
100
200
300
AST
ALT
TBIL
(10) 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 
Day aer L-AMB therapy start 
0
2000
4000
6000
8000
10000
12000
0
1000
2000
3000
4000
EOSI
WBC
NE
0
5
10
15
CRP
Fig. 1 a Treatment history and laboratory data. The duration of antibiotic treatment is shown by the block bars
Page 3 of 4Hagihara et al. BMC Res Notes  (2015) 8:510 
there was no sore. She also had cervical and inguinal lym-
phadenopathy. All antimicrobial therapies were stopped 
as being the most likely cause 20 days after from re-start 
of L-AMB therapy.
Laboratory examination revealed the following abnor-
malities: an elevated C-reactive protein (5.08  mg/dL), 
increased white cell count (6300 cells/mm3) and eosino-
phil (2929 cells/μl), elevated liver enzymes (aspartate 
aminotransferase 280 U/l; alanine transferase 224 U/l), 
and decreased estimated glomerular filtration rate; eGFR 
(75  mg/min). Additionally, as differential diagnosis for 
fever, rush, virus infection and increment of rheumatism, 
we investigated some other examinations. Consequently, 
myeloperoxidase-antineutrophil cytoplasmic antibody 
(MPO-ANCA) was negative (<1.0 U/ml). Ferritin was 
230.7 ng/ml (negative for adult onset Still’s disease). Anti-
body titres against Human Parvovirus B19 (HPV/B19) 
IgM was not increased (0.30: upper range is 0.8). Human 
T-lymphotropic Virus-1 (HTLV-1) was negative. Arthri-
tis and MMR-3 were negative.
A DRESS syndrome was suspected based on the diag-
nostic criteria for DRESS defined and used by the Inter-
national Regi-SCAR-group and published by Kardaun 
et al. [1, 2]. The score was 6, which classified as “possible, 
probable, or defined”. Additionally, we admitted hypere-
osinophilia in here laboratory test especially right after 
second L-AMB therapy started. Her fever went down and 
the eruption disappeared completely after over 3  weeks 
from all antibiotic therapy stopped, respectively. We 
admitted long-lasting skin eruptions in combination with 
visceral involvement, as one of the typical characters of 
DRESS. Liver enzyme levels also returned gently to the 
normal level.
Discussion
DRESS is a severe, cutaneous reaction to drugs leading 
to long-lasting skin eruptions in combination with vis-
ceral involvement. The hallmark features include a dif-
fuse maculopapular rash, exfoliative dermatitis, facial 
edema, lymphadenopathy, fever, multivisceral involve-
ment, eosinophilia, and lymphocytosis [12]. In general, 
one of the most common causative drugs is antiepileptic 
drug. However, the patient had not taken any antiepilep-
tic drugs previously.
L-AMB is an antifungal drug that inhibits fungal cell 
wall synthesis, which is mainly used for treatments of 
Candida spp. and Aspergillus spp. infections. The use of 
L-AMB is increasing in medical setting because of its tol-
erability and potent fungicidal activity [13].
In this case, we admitted some typical symptom of 
DRESS including eosinophilia, and lymphocytosis, while 
atypical lymphocytes were not detected. We believe that 
L-AMB was the culprit drug in view of a clear tempo-
ral relationship between L-AMB administration and the 
onset of symptoms (45  days, typically 2–6  weeks) [14], 
the remission of the symptomatological pattern after 
L-AMB withdrawal. Additionally, she had been admit-
ted allergic reactions right after L-AMB re-start. Only 
L-AMB was re-used when eosinophilia was admitted for 
this patient, while many other antibiotics were used at 
the same time. Finally, based on the Naranjo algorithm, 
it suggested that the systemic reaction was due to L-AMB 
[15].
As allergic reactions to L-AMB were previously 
reported [16], some researchers have shown that lipo-
protein association of drug compounds can significantly 
influence not only the pharmacological and pharmacoki-
netics of the drug, but also the relative toxicity. In phar-
macokinetics study of L-AMB, the drug showed higher 
transferability to the liver, and its half-life of L-AMB 
concentration in the liver was much longer than that of 
L-AMB concentration in the blood [11]. Moreover, the 
L-AMB’s long half-life in the liver is also much longer 
than other co-administrated drugs. Probably, this is the 
reason of long-lasting allergic symptoms.
However, our speculation has some limitations. First, 
while many articles have reported that DRESS might be 
associated with human herpes virus (HHV-6), Epstein-
Barr virus (EBV), cytomegalovirus (CMV) reactivation 
[4, 17], these reactivation were not conducted. And patch 
test and the lymphocyte transformation test (LTT) were 
not investigated in this case. But, the Regi-SCAR-Group 
Diagnosis Score was 6 [1, 2]. Hence, it is highly possible 
that this patient could be diagnosed with DRESS. How-
ever, long half-life of the drug concentration in tissue of 
L-AMB and, on the stand points of timing, the drug was 
highly suspicious.
Conclusions
The present case report shows that prolonged L-AMB 
treatment can be associated with DRESS. The use of 
L-AMB is increasing in medical setting because of its tol-
erability and potent fungicidal activity. The greater use 
of L-AMB may result in an increase in the incidence of 
L-AMB-related adverse effects, while L-AMB is known 
Fig. 2 a, b A macropapular eruption with purpura was present on 
the upper arm
Page 4 of 4Hagihara et al. BMC Res Notes  (2015) 8:510 
to have a wide margin of safety [11]. Thus, we recom-
mend careful monitoring of neutrophil counts in a pro-
longed treatment course with L-AMB.
Consent
Written informed consent was obtained from the patient 
for publication of this Case Report and any accompany-
ing images. A copy of the written consent is available for 
review by the Editor-in-Chief of this journal.
Abbreviations
L-AMB: Liposomal amphotericin-B; DIHS: Drug-induced hypersensitivity 
syndrome; DRESS: Drug rash with eosinophilia and systemic symptoms; MIC: 
Minimum inhibitory concentration; CLSI: Clinical and laboratory standards 
institute; SAH: Subarachnoid hemorrhage; F-FLCZ: Fosfluconazole; 5-FC: 5-flu-
cytosin; MPO-ANCA: Myeloperoxidase-antineutrophil cytoplasmic antibody; 
HPV/B19: Human parvovirus B19; HTLV-1: Human T-lymphotropic virus-1; EBV: 
Epstein-barr virus; CMV: Cytomegalovirus; LTT: Lymphocyte transformation 
test.
Authors’ contributions
MH, YY and HM contributed to writing the manuscript. YY, JH, YK and HM were 
the attending physician, gathered patient information. MH, HK, YH and KM 
were the attending pharmacist, gathered patient information. All the authors 
read and approved the final version of the manuscript.
Author details
1 Department of Infection Control and Prevention, Aichi Medical University 
School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan. 
2 Department of Pharmacy, Aichi Medical University School of Medicine, Naga-
kute, Aichi 480-1195, Japan. 
Acknowledgements
We thank all member of infection control team in Aichi medical university 
hospital, for editing the manuscript.
Compliance with ethical guidelines
Competing interests
The authors declare that they have no competing interests.
Received: 6 May 2015   Accepted: 21 September 2015
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Drug-induced hypersensitivity syndrome by liposomal amphotericin-B: a case report

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Drug-induced hypersensitivity syndrome by liposomal amphotericin-B: a case report

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